Through their control of neuronal excitability, potassium channels can alter synaptic transmission and regulate the neuronal communication that underlies the essence of all behavior. In recent years, the calcium-activated potassium channel (Slo), which plays a particular role in repolarization and, thus, neurotransmission at the neuronal synapse, has been shown to assemble with a variety of proteins that modulate its activity. Aim 1 of this proposal seeks to further explore our preliminary evidence for a binding interaction between synuclein proteins and the Slo channel via biochemical techniques such as yeast two-hybrid, and to elucidate the exact protein domains that mediate such binding by molecular biological and biochemical techniques. The goal of the second Aim is to determine the functional significance of a synuclein-Slo interaction by means of electrophysiology in heterologous co-expression systems. If the electrophysiological effects in heterologous cells are promising, then genetic approaches will be used to test for in situ effects of Slo modulation by synuclein at the Drosophila neuromuscular junction. Synuclein proteins themselves have been implicated in synaptic function through their association with synaptic vesicles and their upregulation during synaptic plasticity (for review, see Clayton and George, 1999). A better understanding of the proteins that orchestrate the events of neurotransmission will not only lead to the knowledge of the mechanisms underlying such complex behaviors as movement coordination and memory, but may also lead to an understanding of the malfunctions that occur in synuclein-related neuropathies (for review, see Goedert, 1999).